When the On-Off Switch is Molecule-Size: A Professor’s Search

In the quest to unravel the mysteries of mental disorders such as depression and schizophrenia, Marija Kundakovic, Ph.D., is harnessing the power of epigenomics.

Kundakovic, an assistant professor of biological sciences, is conducting research to understand the mechanisms that drive the behavior of genes. Although the genes in humans are similar, individual genes can “express” themselves in different ways, through either alteration of the DNA or of the proteins that hold the DNA together.

“What makes something a brain cell, a skin cell, or a blood cell? The genetics are the same, meaning the set of genes that we have are the same,” she said. But within that set, “different genes are turned on or off. So, depending on which genes you turn on or off, certain cells will function as say, neurons, blood cells, or something else.”

When spread out, human DNA is actually about six-and-a-half feet long, said Kundakovic. To fit it into a microscopic structure called a nucleus, it’s wrapped into a structure called a chromatin. In this process, some DNA is squeezed tightly together; some not. Kundakovic compared the way DNA is wrapped to a library where some books are accessible while others are stored on shelves that are off limits.

Opening up parts of that “library” i.e., the human genome, to change could lead to developments like cancer or psychiatric disorder, said Kundakovic. There are some life periods with more flexibility and, hence, vulnerability than others, and this is particularly important during human development. The DNA and proteins are susceptible to outside environmental factors that a person might encounter early in life—Kundakovic’s work lies at this level.

Previously at Columbia University, her research showed a connection between exposure to certain kinds of plastics and fetal development. Now, she is looking for connections between abuse and neglect early in life, and depression and anxiety later on in adulthood.

It’s already known that the former often leads to the latter, but researchers don’t fully understand the underlying processes that cause it.

“If there is early-life neglect or abuse, chances are that later in life, the person will be socially isolated. We’re trying to understand whether these two stressful events actually are interacting,” Kundakovic said.

Her current study on mental disorders, which is funded by the Brain and Behavior Research Foundation, is just getting underway.

What makes Kundakovic’s work particularly challenging is the fact that the changes that she’s looking for are in the brain, and therefore, inaccessible in living subjects. So she has to look for clues somewhere other than in brain cells, for example blood cells.

“If I take a blood cell, and I see some differences in autistic children versus control children, or ADHD children versus control children, what does that mean for the brain? It might not exactly reflect what’s happening in the brain, but I do believe there is a lot of potential here,” she said.

“The idea is that environmental exposures like stress or malnutrition can leave a signature in the peripheral tissues that can capture something also happening in the brain.”

In addition to blood cells from living subjects, Kundakovic has also received post mortem brain tissue for a separate project that will compare the epigenome of neuronal and non neuronal cells. This is important because even within the brain, not every cell is identical. Epigenomes vary not only among cells, but also among different individuals. Successful studies require hundreds of patients, and take a long time, particularly since the field of epigenetics is relatively new.

Kundakovic is hopeful that scientists will be able to identify biomarkers for serious psychiatric disorders before the disorders take hold. There will never be just one on/off switch that will predict whether everyone will be afflicted by depression; rather she envisions a panel of markers that will tip off scientists to a person’s risks.

“There will be genetic markers, there will be epigenetic markers, and you might see brain-imaging markers. We will probably need to have several different tests to be able to predict whether someone will develop this.

“I’m not naïve enough to think epigenetics is everything,” she said. “I just think it’s an important part of neuroscience, and it is very important to understand this in the context of psychiatric disorders.”

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